Chronic hypoxia in cultured human podocytes inhibits BKCa channels by upregulating its β4-subunit

Accumulating evidence suggests that podocyte hypoxia is an alternative mechanism for the pathogenesis of renal diseases. Functional, large-conductance, calcium-activated potassium channels (BKCa channels) are expressed in podocytes as mechanosensitive channels; however, whether BKCa channels are involved in the podocyte response to chronic hypoxia and the possible underlying mechanisms remain unclear. Here, we use the patch clamp technique to show that the exposure of human podocytes to 2% O-2 for 24 h causes a significant reduction in BKCa channel currents. Molecular biology experiments showed that chronic hypoxia increased BKCa channel beta 4-subunit mRNA and protein expression, but not the expression of the BKCa pore-forming alpha- or beta-subunits. Furthermore, chronic hypoxia shifted the channel activation range toward more depolarized voltages and slowed its activation kinetics, which are similar to the properties conferred by the beta 4-subunit. We conclude that BKCa channels are involved in the response of podocytes to chronic hypoxia via the upregulation of the beta 4-subunit. These findings provide new insight into the mechanism underlying the cellular responses of podocytes to hypoxia. (C) 2012 Elsevier Inc. All rights reserved.